Neurotoxicity

The most important individual and public health danger posed by the widespread use of MDMA is the likelihood that it causes the permanent destruction of serotonin axons in humans who use it. The ingestion of MDMA in laboratory animals causes a decrease in the serum and spinal fluid levels of 5-HIAA in a dose-dependent fashion (McCann et al., 2000; Shulgin, 1990) and damages brain serotonin neurons (Burgess, McDonoghoe, & Gill, 2000; McCann & Ricaurte, 1993; Montoya, Sorrentino, Lucas, & Price, 2002). The dosage necessary to cause permanent damage to most rodent species is many times greater than that normally ingested by humans (Shulgin, 1990). In nonhuman primates, the neurotoxic dosage approximates the recreational dosage taken by humans (McCann & Ricaurte, 1993). A recent study by Ricaurte and McCann (2001), which reported an alarmingly small dose necessary for the neurotoxicity to occur, has subsequently been retracted due to a human error in the laboratory (Walgate, 2003). Nevertheless, like its close structural relative methyl-enedioxyamphetamine (MDA, or "Eve"), MDMA has been found to damage serotonin neurons in all animal species tested to date (McCann, Slate, & Ricaurte, 1996), and the same is likely to occur in humans.

MDMA produces a 30-35% drop in serotonin metabolism in humans (McCann et al., 1994). Even one dose of MDMA may cause lasting damage to the serotonin system. There are many reports of individuals with lasting neuro-psychiatric disturbances after MDMA use (Cohen, 1998; Creighton, Black, & Hyde, 1991; McCann & Ricaurte, 1991; Schifano, 1991). Such damage might become apparent only with time or under conditions of stress. Users with no initial complications may manifest problems over time (McCann et al., 1996).

For obvious reasons of safety and ethics, human studies are more difficult to execute, and those that are done offer legitimate and ample room for criticism. The bulk of evidence that MDMA is neurotoxic in humans is indirect but convincing (Burgess et al., 2000; Green et al., 1995). This evidence includes metabolite studies, which quantify the levels of serotonin and metabolites in populations of Ecstasy users. An increasing number of investigations demonstrate that metabolite levels of serotonin are much lower in chronic users, even when abstinent for long periods of time. The difficulties of the studies notwithstanding, the available clinical evidence suggests that repeated ingestion of high doses of MDMA produces long-term reductions in serotonergic activity and degeneration of serotonergic terminals in humans (Montoya et al., 2002).

Extensive cognitive studies in individuals using MDMA, though rife with methodological problems, show a consistent pattern of cognitive dysfunction seen in the frontal cortex and the hippocampus. This phenomenon is consistent with that found in animals exposed to MDMA (Fox, Parrott, & Turner, 2001; Montoya et al., 2002). Psychiatric problems, such as depression, anxiety, panic, increased impulsiveness, and sleep disturbances, are significantly higher in MDMA users, even when users are abstinent and the last use is remote. In a symposium ("Is MDMA a Human Neurotoxin?"), Turner and Parrott (2000) concluded: "Novel studies . . . confirmed and extended the range of cognitive, behavioral, EEG, and neurological deficits, displayed by drug-free Ecstasy users. Moreover, these deficits often remained when other illicit drug use was statistically controlled. In conclusion: If MDMA neurotoxicity in humans is a myth, then it is a myth with a heavy serotonergic component." A recent study by Ricaurte, Yuan, Hatzidiitrious, Cord, and McCann (2002) implicated MDMA as causal of dopaminergic neurotoxicity as well. The involvement of the dopa-mine system has important implications in terms of increased vulnerability to a variety of motor and cognitive functions. Some of the more dramatic results of the work of Ricaurte have recently been thrown into doubt and are controversial, but the basic results of his and others' work are still considered consistent. This is a general chapter dealing with all aspects of club drugs and MDMA. The reader is directed to several excellent and extensive reviews of the particular subject of MDMA and neurotoxicity (McCann et al., 2000; Montoya et al., 2002; Verkes et al., 2001).

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